Process for the manufacture of tetrasubstituted ureas

ABSTRACT

A process for the manufacture of N,N,N&#39;&#39;,N&#39;&#39;-tetrasubstituted ureas of the general formula   in which R1 to R4 each represent an alkyl radical, with R1 and R2 and R3 and R4 in each case together with the nitrogen atom to which they are bonded, being able to form a heterocyclic ring which may optionally contain further hetero atoms, wherein N,Ndisubstituted carbamic acid halides of the formula   in which R1 and R2 have the meaning given above and X represents a halogen atom, especially chlorine or bromine are reacted with a secondary amine and an inorganic base, preferably anhydrous ammonia and the new N,N,N&#39;&#39;,N&#39;&#39;-tetrasubstituted ureas.

United States Patent [1 1 Somlo 51 Sept. 9, 1975 PROCESS FOR THE MANUFACTURE OF TETRASUBSTITUTED UREAS [75] Inventor: Tibor S0ml0,Birsfelden,

Switzerland [73] Assignee: Ciba-Geigy Corporation, Ardsley,

221 Filed: Feb.ll, 1972 211 Appl.No.:225,625

[30[ Foreign Application Priority Data Feb. I6, 1971 Switzerland 2247/71 Jan. 20. 1972 Switzerland 824/72 [52] U.S. Cl. 260/239 E; 260/239 BF; 260/246 B; 260/2472 A; 260/293.63; 260/293.76;

[51] Int. Cl. C07D 203/00 [58] Field of Search... 260/553 R, 553 A, 247.2 A, 260/293.63, 246 B, 326.4, 326.25, 239 E,

[56] References Cited UNITED STATES PATENTS 2,659,747 ll/l953 Young 260/461 3555086 l/l97l Wcis ct a1. 260/553 R 3,714,217 l/l973 Sturm ct al. 260/553 R Primary Exuminer-Donald G. Daus Assistant ExaminerJose Tovar Attorney, Agent, or Firm.loseph G. Kolodny; Prabodh I. Almaula; Edward McC. Roberts [57] ABSTRACT A process for the manufacture of N,N,N',N- tetrasubstituted ureas of the general formula in which R and R have the meaning given above and X represents a halogen atom, especially chlorine or bromine are reacted with a secondary amine and an inorganic base, preferably anhydrous ammonia and the new N,N,N',N'-tetrasubstituted ureas.

9 Claims, No Drawings PROCESS FOR THE MANUFACTURE OF TETRASUBSTITUTED UREAS The present invention relates to tetrasubstituted ureas of the general formula wherein R, to R, each represent an alkyl radical with R, and R and R and R in each case, together with the nitrogen atom to which they are bonded, being able to form a heterocyclic ring which optionally contains further hetero atoms, for example oxygen. sulphur or nitrogen atoms.

The alkyl radicals R to R, may contain a smaller or greater number of carbon atoms; they may be straightchain or branched. They may also contain aryl radicals, for example a benzyl radical. Compounds to which interest attaches are primarily those of the formula l in which R, to R, are alkyl radicals containing from I to 18 carbon atoms. Where R, and R and R,, and R in each case together with the nitrogen atom to which they are bonded form a heterocyclic ring, compounds of the formula A (('H NC()N icH i (2) or mixed" ureas of the formula a (can. N co i-i (3;

are preferred, in which n and m are positive integers from 2 to 6 and R and R, each represent an alkyl radical. Compounds of the formulae (2) and (3) may contain. for example, aziridine. pyrrolidine, piperidine or hexamethyleneimine radicals bonded to the carbonyl bridge. If the heteroeyclic ring formed by R, and R and R,, and R, in each case together with the nitrogen atom to which they are bonded contains a further heteroatom in addition to the nitrogen atom. suitable compounds are primarily those of the formulae (ill wherein X has the meaning given hereinabove. The morpholino radical may be cited as a example of radical of the formula (7).

The present invention relates also to a process for the manufacture of the tetrasubstituted ureas described hereinabove.

The tetrasubstituted ureas may be manufactured according to various methods.

The method generally employed is the reaction of N.N-disubstituted carbamic acid halides with secondary amines and which proceeds according to the equation The disadvantages of this process are that 2 mols of amine are required to manufacture 1 mol of urea. that the pronounced heat effect of the reaction is technically difficult to control. and that. in certain circumstances. it is difficult to isolate the resulting urea from the salts that have formed. Other known methods likewise have disadvantages, for example the formation of troublesome by-products or an undesirable consumption of additional and possibly expensive reactants.

The discovery has now been made that it is possible to manufacture tetrasubstituted ureas by a method which does not possess the disadvantages of the known methods. This process constitutes a development of a process we have discovered for the manufacture of N.N-disubstituted carbamic acid halides.

The process according to the invention consists in reacting an N,N-disubstituted carbainic acid halide. in particular a chloride. of the formula with a secondary amine of the formula .HN on and a base. in particular anhydrous ammonia without solvent. in the tetrasubstituted urea to be manufactured as solvent. or in concentrated aqueous solution. preferably between about 2()C and 120C.

The reaction proceeds, for example. according to the empirical equations nia. The surprising discovery has now been made that the dialkylcarbamic chlorides, in the presence of ammonia and secondary aliphatic amines, react selectively only with the latter.

earth hydroxides and carbonates, or ammonium hydroxide. Preferably in this case also the reaction takes place continuously. On account of the pronounced heat effect, it is advisable to use a reaction vessel which The dialkylc rbamic chl ride, whi h i .prepared 5 permits a good heat exchangev The process is preferafrom dialkylaminc and phosgene, is advantageously rebly carried out at low temperatures, from about 2()C acted in a first reaction step with an approximately to C. The secondary amine and the base may be equivalent amount of dialkylamine, and the mixture is added simultaneously and continuously to the cartreated in a second step with ammonia. The ammonia bamic chloride. Subsequent upon the reaction. the is advantageously introduced in gaseous form. The re 10 water contained in the reaction solution is distilled off action may be illustrated as follows: continuously and the tetrasubstituted urea formed is The process is preferably carried out at 40C to 70C. filtered off from precipitated alkali or alkaline earth The ammonium chloride is precipitated quantitatively chloride. in the form of coarse crystals. The ammonia gas intro- The resulting product is the practically pure urea deduced in the second step does not react with the free rivativev The reaction is carried out at a pH between dialkylcarbamic chloride present, but liberates the about 9 and 11.5. preferably between I() and ll. dialkylamine from its salt, whereupon this latter reacts Examples of suitablestarting materials for the prowith the dialkylcarbamic chloride. No dialkyl urea is cess according to the invention are: formed. The reaction is generally carried out in a N,N-disubstitutcd carbamic chlorides closed system; and the completion ofthe reaction is de- N,N-dimethylcarbamic chloride, tected by no more ammonia gas being taken up (sig- N.Ndiethylcarbamic chloride. nalled by a rise in pressure in the reaction vessel). It is N,N-diisobutylcarbamic chloride, also possible to treat the carbamic chloride simulta- N.N-diisoamylcarbamic chloride, neously with dialkylamine and ammonia. N.N-diisoheptylcarbamic chloride.

Upon completion of the reaction. the mixture is alpyrrolidinocarbamic chloride. lowed to cool to room temperature and the urea is isopipfiri ino llll' llmi Chloride. lated by filtration from the crystalline ammonium chlomorpholinocarbamic Chlori ride. It is possible to isolate a further amount of urea by N.N-dibenzylcarbamic chloride. extracting the ammonium chloride residue with sol- \'IN Ih)/I H Chloride. vents, such as methylene chloride, benzene, toluene -m hy -N-cyclohexylcarbamic chloride. etc. and concentrating the extracts. Yields of over 95% Secondary ilmillesi of th are bt i d i hi maimen dimethylamine, diethylamine, dibutylamine,

The use of anhydrous ammonia as acid binding agent diiwhutylilminm mcthykcthylumlnc diisoumyluminct offers particular advantages: the heat effect of the reacdiisohcptylllmim- P P l morphollntion is easily controllable, since the formation of amdlhcnzylumlnt nmthylcyclohcXylilmlnc monium chloride is less exothermic than that of water Instead of the chlorides cited hereinabove, it is also if sodium hydroxide, for example, is u ed as b e possible to use other halides of N.N-disubstituted car- Moreover, the processing of the reaction mixture is hl mi acids. f r in n romides. very simple, since it is necessary to isolate only the am- The process according to the invention may be admonium chloride occurring in the form of coarse crysuntag usly combined with the process which has altails and no water need be distilled off. Preferably the ready been mentioned for the manufacture of N.N- reaction takes place continuously, and virtually pure disubstitutcd Carbamic acid halides. tetrasubstituted urea is obtained. In this process. N.N-disubstituted carbainic chlorides Instead of anhydrous ammonia, it is also possible to of the formula use as acid binding agents bases differing from the dials kyl amine used, in particular inorganic bases, for example alkali hydroxides, especially concentrated aqueous sodium hydroxide solution, alkali carbonates, alkaline are obtained in very good yield by reacting a secondary amine of the formula (R R )NH with phosgcne in high boiling solvents. or. preferably. in the carbamic chloride to be manufactured itself as solvent. at elevated temperature (between about 60C and 160C). prcferably at 80C to 95C. The amine and the phosgene are advantageously added together simultaneously and continuously, the phosgene being present in an excess of 5 to lll /r conditioned by factors relating to the technical apparatus used. Preferably, the process is carried out continuously. The reaction takes'place in a reaction vessel equipped with stirrer and in which there is present a solvent, or preferably the desired carbamic chloride from a previous batch as solvent. On simultaneously running in the amine and introducing the phosgene. the reaction proceeds of its own accord at corre sponding temperature. The carbamic chloride formed is continuously discharged into a second vessel. The resulting crude product is sufficiently pure to enable it to be used without further processing for the reaction with a secondary amine to give the tetrasubstituted urea.

The N.Ndisubstituted carbamic chloride which occurs in the manner described can now likewise continuously be passed into a second reaction vessel in which it is reacted with a secondary amine. The reaction mixture obtained can then be treated with ammonia gas in a third reactor. The viscous suspension is centrifuged or thoroughly filtered with suction under vacuum. The filtrate consists of practically pure tetrasubstituted urea. The introduction of gaseous secondary amine or gaseous ammonia takes place in a closed system. preferably under slight overpressure to 40 mm g).

On using bases other than anhydrous ammonia. the N.N-disubstituted carbamic chloride manufactured in the manner described may be conveyed in turn to a reaction vessel into which the secondary amine and the required amount of base. for example sodium hydroxide. are introduced simultaneouslyu The pH of the reaction solution is kept at the required value by the addition of sodium hydroxide solution. and a severe cooling ensures that the reaction temperature does not exceed 20C. A solution which consists of the desired tetrasubstituted urea. sodium chloride and water may be withdrawn continuously from this reaction vessel. As already mentioned, it is possible to distill off the water under normal pressure and the precipitated sodium chloride can be isolated by filtration from the filtrate, which consists of virtually pure tetrasubstituted urea.

The tetrasubstituted ureas according to the invention are used in preparative organic chemistry as reactants. for example as chlorination catalysts and particularly as solvents in various reactions (see also A ngew. Chemic. 75. I059 1963 However. their industrial use has hitherto been limited on account of the known complicated and expensive manufacturing processes. The present process now makes such urea compounds readily available and thus permits their advantageous properties to be used also for industrial processes.

The following Examples illustratethc invention, the parts and percentages being by weight unlessotherwise stated.

EXAMPLE 1 350 Parts (about 300 ml) of dimethylcarbamic chloride are introduced initially into a reaction vessel of 350 ml capacity. and parts of dimcthylamine gas and 140 parts of phosgene are introduced beneath the surface simultaneously and regularly per hour at C to C, with stirring. The dimethylcarbamic chloride which has formed flows continuously into the second reaction vessel. into which a further 63 parts of dimethylamine gas are steadily passed in simultaneously per hour. By simultaneously adding about 54 parts of 10071 sodium hydroxide solution (in the form of about 4071 solution) per hour the pH in the second reaction vessel is kept at 10.5 to l 1.5. and the reaction temperature kept below 20C by intense cooling. Through the outlet of the second reaction vessel tlhere flow per hour about 310 parts of a solution of the following composition: app. 477r tetramethyl urea, ap pl. 27% water. app. 26% sodium chloride.

The water is distilled off from this solution at normal pressure and the crystallised sodium chloride filtered off. The filtrate is virtually pure tetramethyl urea. which occurs in purity of over 99% and in a yield of 95% (relative to the amount of dimethylamine used).

Boiling point at 10 mm Hg: 62C; refractive index at 20: l.45()() 0 EXAMPLE 2 1075 Parts of dimethylcarbamic chloride are introduced initially into a reaction vessel of 1500 ml capacity and 450 parts of dimethylamine gas are passed in at 5060C with stirring. The gas is introduced in a closed system. in the process of which a slight overpressure (2040 mm Hg) should be present. Subsequently parts of ammonia gas are passed into the reaction mixture. At the conclusion of the reaction. no more ammonia is taken up, so that the pressure in the closed system increases. Stirring is continued for half an hour, the thick suspension cooled to 20C and thoroughly filtered with suction or centrifuged. The filtrate consists of 1050 parts of virtually pure tetramethyl urea. lt is possible to extract a further 60 parts of tetramcthyl urea from the ammonium chloride filter cake with a solvent. for example methylene chloride. toluene ctc. Calculated on the amount of dimethylcarbamic chloride used. the yield thus amounts to 9671 of theory.

EXAMPLE 3 322.5 Parts of dimethylcarbamic chloride are introduced initially into a reaction vessel of 1500 ml capacity and 45 parts of dimcthylamine gas and 108 parts of phosgene are passed in per hour beneath the surface simultaneously and regularly at 859()C with stirring. until a total of 315 parts of dimethylamine gas and 756 parts of phosgene have been passed in within 7 hours. The mixture is then cooled to 50C and a further 450 parts of dimethylamine gas. are passed in at 50-60C with stirring. The gas is introduced in'a closed system. when a slight overpressure (2040 mm Hg) should constantly be present in the reaction vessel. Subsequently. and likewise in a closed system, a further 175 parts of ammonia are passed in. At the conclusion of the reaction, no more ammonia is taken up and the pressure in creases. The viscous suspension is cooled to 20C and thoroughly filtered with suction or centrifuged. The filtrate consists of lOSO parts of virtually pure tetramethyl urea.

EXAMPLE 4 350 Parts (app. 300 ml) of dimethylcarbamic chloride are introduced initially into a reaction vessel of 350 ml capacity and 60 parts ofdimethylamine gas and 140 parts of phosgene are passed in simultaneously and regularly per hour at 85C to 90C with stirring. The dimethylcarbamic chloride which has formed dis charges continuously into two consecutively connected reaction vesselsv In the first reaction vessel. the dimethylcarbamic chloride is reacted in counter current with 60 parts of dimethylamine per hour; and in, the second reaction vessel. with 24 parts of ammonia gas per hour. The viscous suspension which leaves the second reaction vessel is centrifuged. The filtrate consists of virtually pure tetramethyl urea. In this manner. 145 parts of tetramethyl urea are obtained per hour. corresponding to a yield of 93.5% of theory. calculated on pholinocarbamie chloride is used as solvent, dimorpholino urea of the formula is obtained. .On account of the relatively high melting point. the processing of this product differs from Exam- The reaction mixture which contains water and salt is'cxtracted repeatedly with toluene and the toluene solutions are then concentrated. The dimorpholino urea crystallises from the toluene. Melting point:

the amount of dimethylamine used. l5 l4 l-l 42C.

If in Exam le 2 the dimeth 'lamine as is re laced b p y EXAMPLEII an equivalent amount of diethylamine. pyrrolidme or morpholine, the following unsymmetric tetrasub- .lf in Examples 1. 3 and 4. the dimethylamine introstituted ureas are formed: dueed into the second reaction vessel is replaced by an I \ample Amine Product Boiling Point 0 ,H H t .H u 7-1 7. l:\ample Q '\'H N c n. n4 H "4' U h P. l.\;nnp|e h HN N N n l I q ,-t o

'mmple HN 0 ll;;( ll n w.

EXAMPLE 8 equivalent amount ofdibenzylamine. the unsymmetric If in Examples 1. 3 and 4. 162 Parts of diethylamine NNd'mcthyLN N Timemyl urea of the tmmulu are used instead of 100 parts of dimethylamine and the corresponding earbamie chloride is used as solvent. tetra-ethyl urea ot the lormula O (HJ O --('H. (H. o H;.('H. ll (H. .(H H10 is obtained. Boiling point at 0.3 mm Hg: l62l65C.

I claim:

is OhminmL l. A process for the manufacture of a N.N.N.N.-

Boiling puim at 12 mm Hg: Q yield 95,7! of tetrasubstituted urea of the formula theory.

EXAMPLE 9 g R. ll R Di-piperidyl urea U R R If in Examples l. 3 and 4. l8) parts of piperidine are a used instead of l()() arts ofdimeth 'lz *2 g 1nd the wherein R R R and R. are henzvl or alkyl of l to 18 responding earbamic chloride is used as solvent. di-

. carbon atoms. or R1 and R2 or R3 and R4 form. topiperidyl urea ot the formula i 55 gether with the nitrogen atom. aziridino. pyrrolrdnm. O piperidino. hexamethyleneimino or morpholino. comprising the steps of treating a N.Ndisubstituted car- C O bamic acid halide of the formula: (R, \(RQNCOX. wherein X is chlorine or bromine. with a secondary amine of the formula: (R;.)( RUNH. and then with anhydrous ammonia isobtamed. 7 o 2. A process for the manufacture of N.N.N.N-

g g P 13 mm meltmg tetrasubstituted urea of the formula point: 42-43C.

EXAMPLE l0 If in Example 1 there are used parts of morpholine instead of l()() parts of dimethylamine and morwherein R R R and R are benzyl or alkyl of l to 18 carbon atoms, comprising the steps of treating. (a) in a first step a N,N-disubstituted carbamic acid halide of the formula: (R,)(R )NCOX. wherein X is chlorine or bromine, with a secondary amine of the formula: (R;,)(R ,)NH-. and (b) in a second step the resulting reaction mixture with anhydrous ammonia.

3. The process of claim 2. wherein the treatment is carried out under pressure at a temperature in the range of 20 to +l2()C.

4. The process of claim 2, wherein X is chlorine, the treatment is carried out at 40C to 70C;

5. The'process of claim.2, wherein R R R and R, are identicah 6. The process of'claim 4, wherein R R R and R,

are identical.

1 .7. The process of claim 5, wherein R R R and R.

t are methyl:

in the absence of solvent or in the N N;N(,NQ-tetrasubstitutcd urea being manufactured.

9. The process of claim 4. wherein the treatment is carried out in the absence of solvent or in the N,N.N.N'-tetrasubstituted urea being manufactured. 

1. A PROCESS FOR THE MANUFACTURE OF A N,N,N2,N''-TETRASUBSTITUTED UREA OF THE FORMULA
 2. A process for the manufacture of N,N,N'',N''-tetrasubstituted urea of the formula
 3. The process of claim 2, wherein the treatment is carried out under pressure at a temperature in the range of -20* to +120*C.
 4. The process of claim 2, wherein X is chlorine, the treatment is carried out at 40*C to 70*C.
 5. The process of claim 2, wherein R1, R2, R3 and R4 are identical.
 6. The process of claim 4, wherein R1, R2, R3 and R4 are identical.
 7. The process of claim 5, wherein R1, R2, R3 and R4 are methyl.
 8. The process of claim 2, wherein the treatment is carried out in the absence of solvent or in the N,N,N'',N'',-tetrasubstituted urea being manufactured.
 9. The process of claim 4, wherein the treatment is carried out in the absence of solvent or in the N,N,N'',N''-tetrasubstituted urea being manufactured. 